List of Phenyltropanes
Encyclopedia
Such list of phenyltropane
s present many different avenues of research into therapeutic and addiction control depending on their construction and structure-activity relationship
ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's
& Parkinson's
diseases. More recently there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of being among one kind that would make it among others of this substance profile.
Use of a cyclopropyl ester appears to enable better MAT
retention than does the choice of isopropyl
ester.
Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.
.
s.
Biotin
| Compound || X || 2 Group || config || 8 || DA||5-HT||NE
|-
| Brasofensine
|| Cl2 || methyl aldoxime || α,β || NMe || ||||
|-
| Tesofensine
|| Cl2 || ethoxymethyl || α,β || NMe ||65||11||1.7
|-
|NS-2359 (GSK-372,475)|| Cl2 || Methoxymethyl || α,β || NH || || ||
|}
equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize to the energetically more favorable trans configuration. This can also happen to cocaine also.
Bi- and tri-cyclic aza compounds and their uses
| Compound || X || 2 Group || config || 8 || DA||5-HT||NE
|-
| Tropoxane
|| Cl,Cl|| CO2Me ||(racemic) β,β || O ||3.3||6.5||No data
|}
(phenylisothiocyanate) binding ligand
RTI-76: 4-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
(GSK-372,475)
It is well established that electrostatic potential around the para position tends to improve MAT
binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant. Of course, this is not always the case. For an interesting exception to this trend, see the Taxil
document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues which have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.
"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine
, and reboxetine
as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).
Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. , , , and .
Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug which is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT
binding affinity.
class (a category that includes methylphenidate
) or benztropine
class (such as Difluoropine
: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRI
s are far removed from being in the phenyltropane structural family, such as Benocyclidine
or Vanoxerine
.
Phenyltropane
Phenyltropanes were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these...
s present many different avenues of research into therapeutic and addiction control depending on their construction and structure-activity relationship
Structure-activity relationship
The structure–activity relationship is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism...
ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
& Parkinson's
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
diseases. More recently there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of being among one kind that would make it among others of this substance profile.
2-Carboxymethyl esters
Certain phenyltropanes can be used as a smoking cessation aid.Short Name | X | DA | 5HT | NE |
---|---|---|---|---|
WIN 35,065-2 (CPT) | H | 23 | 1962 | 920 |
WIN 35,428 (CFT) | F | 14 | 156 | 85 |
RTI-29 | NH2 | 9.8 | 5110 | 151 |
RTI-31 RTI-31 -2β-Carbomethoxy-3β-tropane is a synthetic analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article, RTI-31 is 64 x the strength of cocaine in terms of its potency to elicit... |
Cl | 1.12 | 44.5 | 37 |
RTI-32 RTI-32 -2β-Carbomethoxy-3β-tropane is a phenyltropane-based cocaine analog that is important in the field of medicinal chemistry for performing SAR.It has similar properties in vitro to related drugs such as RTI-31.... |
Me | 1.71 | 240 | 60 |
RTI-51 RTI-51 -2β-Carbomethoxy-3β-tropane is a semi-synthetic alkaloid in the phenyltropane group of psychostimulant compounds. First publicized in the 1990s, it has not been used enough to have gained a fully established profile. RTI-51 can be expected to have properties lying somewhere in between RTI-31 and... |
Br | 1.69 | 10.6 | 37.4 |
Iometopane (RTI-55) | I | 1.26 | 4.21 | 36 |
RTI-83 RTI-83 -2β-Carbomethoxy-3β-tropane is a phenyltropane derivative which represents a rare example of an SDRI or serotonin-dopamine reuptake inhibitor, a drug which inhibits the reuptake of the neurotransmitters serotonin and dopamine, while having little or no effect on the reuptake of the related... |
Et | 55 | 28 | 4030 |
RTI-298 | –≡–Ph | 3.7 | 46.8 | 347 |
RTI-436 | –CH=CHPh | 3.09 | 335 (31) | 1960 (1181) |
RTI-430 | –C≡C(CH2)2Ph | 6.28 | 2128 (198) | 1470 (886) |
(3,4-Disubstituted phenyl)-tropanes
Compound | X | Y | 2 Position | config | 8 | DA | 5-HT | NE |
RTI-318 | β-naphthyl | CO2Me | β,β | NMe | 0.5 | 0.81 | 20 | |
Dichloropane (RTI-111) | Cl | Cl | CO2Me | β,β | NMe | 0.79 | 3.13 | 18.0 |
RTI-88 [recheck] | NH2 | I | CO2Me | β,β | NMe | 1.35 | 1329 | 320 |
RTI-97 | NH2 | Br | CO2Me | β,β | NMe | 3.91 | 181 | 282 |
RTI-112 RTI-112 RTI-112 is a synthetic stimulant drug from the phenyltropane family. In contrast to RTI-113 which is DAT selective, RTI-112 is a nonselective triple reuptake inhibitor.... |
Cl | Me | CO2Me | β,β | NMe | 0.82 | 10.5 | 36.2 |
RTI-96 | F | Me | CO2Me | β,β | NMe | 2.95 | 76 | 520 |
RTI-295 | Et | I | CO2Me | β,β | NMe | 21.3 | 2.96 | 1349 |
RTI-353 RTI-353 RTI-353 is a phenyltropane derived drug which acts as an SSRI.... (EINT) |
Et | I | CO2Me | β,β | NH | 331 | 0.69 | 148 |
RTI-279 | Me | I | CO2Me | β,β | NH | 5.98 | 1.06 | 74.3 |
RTI-280 | Me | I | CO2Me | β,β | NMe | 3.12 | 6.81 | 484 |
Arylcarboxy
Compound | X | 2 Position | config | 8 | DA | 5-HT | NE |
RTI-122 | I | ||||||
β,β | NMe | 1.50 | 184 | 3,791 | |||
RTI-113 RTI-113 RTI-113 is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor . It has been suggested as a possible substitute drug for the treatment of cocaine addiction... |
Cl | ||||||
β,β | NMe | 1.98 | 2,336 | 2,955 | |||
RTI-277 | NO2 | ||||||
β,β | NMe | 5.94 | 2,910 | 5,695 | |||
RTI-120 RTI-120 -2β-Carbophenoxy-3β-tropane is a phenyltropane derivative which acts as a reasonably selective dopamine reuptake inhibitor, along with weaker inhibition of noradrenaline and serotonin reuptake. It has a reasonably fast rate of occupancy of dopamine transporters in the brain, though slower than... [recheck] |
Me | ||||||
β,β | NMe | 3.26 | 24,471 | 5,833 | |||
RTI-116 | Cl | ||||||
β,β | NMe | 33 | 1,227 | 968 | |||
RTI-203 | Cl | CO2(m-C6H4Me) | β,β | NMe | 9.37 | 2153 | 2744 |
RTI-204 | Cl | ||||||
β,β | NMe | 3.91 | 3,772 | 4,783 | |||
RTI-205 | Me | ||||||
β,β | NMe | 8.19 | 5,237 | 2,137 | |||
RTI-206 | Cl | ||||||
β,β | NMe | 27.4 | 1,203 | 1,278 | |||
Carboxyalkyl
Code | X | 2 Position | config | 8 | DA | 5-HT | NE |
RTI-77 | Cl | CH2CH2(3-iodo-p-anilino) | β,β | NMe | 2.51 | — | 2247 |
RTI-121 RTI-121 -2β-Carboisopropoxy-3β-tropane is a stimulant drug used in scientific research, which was developed in the early 1990s. RTI-121 is a phenyltropane based, highly selective dopamine reuptake inhibitor and is derived from methylecgonidine... |
I | ||||||
β,β | NMe | 0.43 | 66.8 | 285 | |||
RTI-153 | I | ||||||
β,β | NH | 1.06 | 3.59 | 132 | |||
RTI-191 | I | ||||||
β,β | NMe | 0.61 | 15.5 | 102 | |||
RTI-114 | Cl | ||||||
β,β | NMe | 1.40 | 1,404 | 778 | |||
RTI-278 | NO2 | ||||||
β,β | NMe | 8.14 | 2,147 | 4,095 | |||
RTI-190 | Cl | ||||||
β,β | NMe | 0.96 | 168 | 235 | |||
RTI-193 | Me | ||||||
β,β | NMe | 1.68 | 1,066 | 644 | |||
RTI-117 | Me | ||||||
β,β | NMe | 6.45 | 6,090 | 1,926 | |||
RTI-150 | Me | ||||||
β,β | NMe | 3.74 | 2,020 | 4,738 | |||
RTI-127 | Me | ||||||
β,β | NMe | 19 | 4500 | 3444 | |||
RTI-338 | ethyl | ||||||
β,β | NMe | 1104 | 7.41 | 3366 |
Use of a cyclopropyl ester appears to enable better MAT
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...
retention than does the choice of isopropyl
Isopropyl
In organic chemistry, isopropyl is a propyl with a group attached to the secondary carbon. If viewed as a functional group an isopropyl is an organic compound with a propyl group attached at its secondary carbon.The bond is therefore on the middle carbon....
ester.
Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.
Amides
RTI-183 and RTI-218 have the same structure??Code | X | 2 Position | config | 8 | DA | NE | 5-HT |
RTI-106 | Cl | CON(H)Me | β,β | NMe | 12.4 | 1511 | 1312 |
RTI-118 | Cl | CONH2 | β,β | NMe | 11.5 | 4267 | 1621 |
RTI-222 | Me | morpholinyl | β,β | NMe | 11.7 | — | >100K |
RTI-129 | Cl | CONMe2 | β,β | NMe | 1.38 | 942 | 1079 |
RTI-146 | Cl | CONHCH2OH | β,β | NMe | 2.05 | 144 | 98 |
RTI-147 | Cl | CON(CH2)4 | β,β | NMe | 1.38 | 3,949 | 12,394 |
RTI-156 | Cl | CON(CH2)5 | β,β | NMe | 6.61 | 5832 | 3468 |
RTI-170 | Cl | CON(H)CH2C≡CH | β,β | NMe | 16.5 | 1839 | 4827 |
RTI-172 | Cl | CON(H)NH2 | β,β | NMe | 44.1 | 3914 | 3815 |
RTI-174 | Cl | CONHCOMe | β,β | NMe | 158 | >43K | >125K |
RTI-182 | Cl | CONHCH2COPh | β,β | NMe | 7.79 | 1722 | 827 |
RTI-183 | Cl | CON(OMe)Me | β,β | NMe | 0.85 | 549 | 724 |
RTI-186 | Me | CON(OMe)Me | β,β | NMe | 2.55 | 442 (266) | 3400 (309) |
RTI-198 | Cl | CON(CH2)3 | β,β | NMe | 6.57 | 990 | 813 |
RTI-196 | Cl | CONHOMe | β,β | NMe | 10.7 | 9907 | >43K |
RTI-201 | Cl | CONHNHCOPh | β,β | NMe | 91.8 | >20K | >48K |
RTI-208 | Cl | CONO(CH2)3 | β,β | NMe | 1.47 | 998 | 2470 |
RTI-214 | Cl | CON(-CH2CH2-)2O | β,β | NMe | 2.90 | 8545 | >88K |
RTI-215 | Cl | CONEt2 | β,β | NMe | 5.48 | ? | 9432 |
RTI-217 | Cl | CONH(m-C6H4OH) | β,β | NMe | 4.78 | >30K | >16K |
RTI-218 | Cl | CON(Me)OMe | β,β | NMe | 1.19 | 520 | 1911 |
RTI-226 | Cl | CONMePh | β,β | NMe | 45.0 | ? | 24K |
RTI-227 | I | CONO(CH2)3 | β,β | NMe | 0.75 | 446 | 230 |
RTI-229 RTI-229 -3β-tropane-2β-pyrrolidine carboxamide is a potent and long-lasting stimulant drug which was developed in the 1990s as part of a large group of related analogues from the phenyltropane family... |
I | CON(CH2)4 | β,β | NMe | 0.37 | 991 | 1,728 |
Acyl
Code | X | Y | 2 Position | config | 8 | DA | 5-HT | NE |
WF-23 | β-naphthyl | C(O)Et | β,β | NMe | 0.115 | 0.394 | No data | |
WF-31 2-Propanoyl-3-(4-isopropylphenyl)-tropane 2-Propanoyl-3--tropane is a cocaine analogue. Research shows WF-31 to be approximately ten times more potent than cocaine at binding to serotonin and at inhibiting serotonin uptake.- References :... |
||||||||
H | C.O.Et | β,β | NMe | 615 | 54.5 | No data | ||
WF-11 | Me | H | ||||||
β,β | NMe | 8.2 | 131 | No data | ||||
WF-25 | H | H | ||||||
β,β | NMe | 48.3 | 1005 | No data | ||||
WF-33 | 6-MeoBN | C(O)Et | α,β | NMe | 0.13 | 2.24 | No data |
Ester reduction
Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methylcarbonateCarbonate
In chemistry, a carbonate is a salt of carbonic acid, characterized by the presence of the carbonate ion, . The name may also mean an ester of carbonic acid, an organic compound containing the carbonate group C2....
.
Code | X | 2 Position | config | 8 | DA | 5-HT | NE |
RTI-100 | F | |||
β,β | NMe | 47 | 4741 | no data |
RTI-101 | I | |||
β,β | NMe | 2.2 | 26 | no data |
RTI-99 | Br | |||
β,β | NMe | 1.49 | 51 | no data |
RTI-93 | Cl | |||
β,β | NMe | 1.53 | 204 | 43.8 |
RTI-105 | Cl | |||
β,β | NMe | 1.60 | 143 | 127 |
RTI-123 | Cl | |||
β,β | NMe | 1.78 | 3.53 | 393 |
RTI-145 | Cl | |||
β,β | NMe | 9.60 | 2.93 | 1.48 |
Misc.
Code | X | 2 Position | config | 8 | DA | 5-HT | NE |
RTI-102 | I | CO2H | β,β | NMe | 474 | 1928 | 43,400 |
RTI-103 | Br | CO2H | β,β | NMe | 278 | 3070 | 17,400 |
RTI-104 | F | CO2H | β,β | NMe | 2744 | >100K | >100K |
RTI-108 | Cl | ||||||
β,β | NMe | 2.64 | 98 | 129.8 | |||
RTI-241 | Me | ||||||
β,β | NMe | 1.02 | 619 | 124 | |||
RTI-139 | Cl | ||||||
β,β | NMe | 1.67 | 85 | 57 | |||
RTI-161 | Cl | ||||||
β,β | NMe | 13.1 | 1887 | 2516 | |||
RTI-230 | Cl | H3C–Ç=CH2 | β,β | NMe | 1.28 | 57 | 141 |
RTI-240 | Cl | ||||||
β,β | NMe | 1.38 | 38.4 | 84.5 | |||
RTI-145 | Cl | ||||||
β,β | NMe | 9.60 | 2,932 | 1,478 | |||
RTI-158 | Me | ||||||
β,β | NMe | 57 | 5095 | 1624 | |||
RTI-131 | Me | ||||||
β,β | NMe | 10.5 | 855 | 120 | |||
RTI-164 | Me | ||||||
β,β | NMe | 13.6 | 2246 | 280 | |||
RTI-132 | Me | ||||||
β,β | NMe | 3.48 | 206 | 137 | |||
RTI-239 | Me | ||||||
β,β | NMe | 0.61 | 114 | 35.6 | |||
RTI-338 | Et | ||||||
β,β | NMe | 1104 | 7.41 | 3366 | |||
RTI-348 | H | ||||||
β,β | NMe | 28.2 | >34,000 | 2670 |
F&B series
The compound of the present invention are useful pesticidePesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...
s.
Code | X | 2 Position | config | DA | NE | 5-HT |
RTI-224 | Me | F1c | β,β | 4.49 | — | 155.6 |
RTI-233 | Me | F2 | β,β | 4.38 | 516 | 73.6 |
RTI-235 | Me | F3 d | β,β | 1.75 | 402 | 72.4 |
RTI-236 | Me | B1 d | β,β | 1.63 | 86.8 | 138 |
RTI-237 | Me | B2 d | β,β | 7.27 | 258 | 363 |
RTI-244 | Me | B3 d | β,β | 15.6 | 1809 | 33.7 |
RTI-245 | Cl | F4 c | β,β | 77.3 | — | — |
RTI-246 | Me | F4 c | β,β | 50.3 | 3000 | — |
RTI-248 | Cl | F6 c | β,β | 9.73 | 4674 | 6.96 |
RTI-249 | Cl | F1 c | β,β | 8.32 | 5023 | 81.6 |
RTI-266 | Me | F2 | β,β | 4.80 | 836 | 842 |
RTI-267 | Me | F7 wrong | β,β | 2.52 | 324 | 455 |
RTI-268 | Me | F7 right | β,β | 3.89 | 1014 | 382 |
RTI-269 | Me | F8 | β,β | 5.55 | 788 | 986 |
Biotin
Biotin
Biotin, also known as Vitamin H or Coenzyme R, is a water-soluble B-complex vitamin discovered by Bateman in 1916. It is composed of a ureido ring fused with a tetrahydrothiophene ring. A valeric acid substituent is attached to one of the carbon atoms of the tetrahydrothiophene ring...
β,α Stereochemistry
Compound | X | 2 Group | config | 8 | DA | 5-HT | NE |
RTI-140 | H | CO2Me | β,α | NMe | 101 | 5,701 | 2,076 |
RTI-352 RTI-352 RTI-352 is a phenyltropane that is used as a radiolabeling ligand for the DAT. RTI-352 has been configured to have 1R,2S,3R stereochemistry and is therefore a geometric isomer of β-CIT.... |
I | CO2Me | β,α | NMe | 2.86 | 64.9 | 52.4 |
RTI-549 | Br | CO2Me | β,α | NMe | |||
RTI-319 | BN | CO2Me | β,α | NMe | 1.1 | 11.4 | 70.2 |
RTI-286 | F | CO2Me | β,α | NMe | 21 | 5062 | 1231 |
RTI-274 RTI-274 RTI-274, or 2β--3α-nortropane is a phenyltropane homologue of paroxetine developed by the group led by F Ivy Carroll in the 1990s.-Introduction:... |
F | CH2O(3'4'-MD-phenyl) | β,α | NH | 3.96 | 5.62 | 14.4 |
RTI-287 | Et | CO2Me | β,α | NMe | 327 | 1687 | 17,819 |
α,β Stereochemistry
{| class="wikitable"| Compound || X || 2 Group || config || 8 || DA||5-HT||NE
|-
| Brasofensine
Brasofensine
Brasofensine is a phenyltropane that had been under development for the treatment of Parkinson's and Alzheimer's disease...
|| Cl2 || methyl aldoxime || α,β || NMe || ||||
|-
| Tesofensine
Tesofensine
Tesofensine is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity...
|| Cl2 || ethoxymethyl || α,β || NMe ||65||11||1.7
|-
|NS-2359 (GSK-372,475)|| Cl2 || Methoxymethyl || α,β || NH || || ||
|}
Heterocycles
These heterocycles are sometimes referred to as the "bioisostericBioisostere
In medicinal chemistry, bioisosteres are substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to a chemical compound. In drug design, the purpose of exchanging one bioisostere for another is to enhance the desired biological or...
equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize to the energetically more favorable trans configuration. This can also happen to cocaine also.
3-Substituted-isoxazol-5-yl
Code | X | R | DA | NE | 5HT |
---|---|---|---|---|---|
RTI-165 | Cl | 3-methylisoxazol-5-yl | 0.59 | 181 | 572 |
RTI-171 RTI-171 -2β--3β-tropane is a phenyltropane derivative which acts as a selective dopamine reuptake inhibitor, with a relatively slow onset of action and short duration of effects found in animal studies.... |
Me | 3-methylisoxazol-5-yl | 0.93 | 254 | 3818 |
RTI-180 | I | 3-methylisoxazol-5-yl | 0.73 | 67.9 | 36.4 |
RTI-177 RTI-177 RTI-177 is a synthetic stimulant drug from the phenyltropane family, which acts as a DRI with micromolar affinity for the SERT... |
Cl | 3-phenylisoxazol-5-yl | 1.28 | 504 | 2418 |
RTI-176 | Me | 3-phenylisoxazol-5-yl | 1.58 | 398 | 5110 |
RTI-181 | I | 3-phenylisoxazol-5-yl | 2.57 | 868 | 100 |
RTI-184 | H | methyl | 43.3 | — | 6208 |
RTI-185 | H | Ph | 285 | — | >12K |
RTI-334 | Cl | 3-ethylisoxazol-5-yl | 0.50 | 120 | 3086 |
RTI-335 | Cl | isopropyl | 1.19 | 954 | 2318 |
RTI-336 | Cl | 3-(4-methylphenyl)isoxazol-5-yl | 4.09 | 1714 | 5741 |
RTI-337 | Cl | 3-t-butyl-isoxazol-5-yl | 7.31 | 6321 | 37K |
RTI-345 | Cl | p-chlorophenyl | 6.42 | 5290 | >76K |
RTI-346 | Cl | p-anisoyl | 1.57 | 762 | 5880 |
RTI-347 | Cl | p-fluorophenyl | 1.86 | 918 | 7257 |
RTI-354 | Me | 3-ethylisoxazol-5-yl | 1.62 | 299 | 6400 |
RTI-366 | Me | R = isopropyl | 4.5 | 2523 (1550) | 42,900 (3900) |
RTI-371 RTI-371 3β--2β-[3-isoxazol-5-yl]tropane is a phenyltropane derived drug which acts as a potent and selective dopamine reuptake inhibitor in vitro, yet unusually for this class of compound, both RTI-371 and the closely related compound RTI-370 failed to produce locomotor stimulation in mice... |
Me | p-chlorophenyl | 8.74 | >100K (60,200) | >100K (9090) |
RTI-386 | Me | p-anisoyl | 3.93 | 756 (450) | 4027 (380) |
RTI-387 | Me | p-fluorophenyl | 6.45 | 917 (546) | >100K (9400) |
3-Substituted-1,2,4-oxadiazole
Code | X | R | DA | NE | 5HT |
---|---|---|---|---|---|
ααRTI-87 | H | 3-methyl-1,2,4-oxadiazole | 204 | 36K | 30K |
βαRTI-119 | H | 3-methyl-1,2,4-oxadiazole | 167 | 7K | 41K |
αβRTI-124 | H | 3-methyl-1,2,4-oxadiazole | 1028 | 71K | 33K |
RTI-125 | Cl | 3-methyl-1,2,4-oxadiazole | 4.05 | 363 | 2584 |
ββRTI-126 | H | 3-methyl-1,2,4-oxadiazole | 100 | 7876 | 3824 |
RTI-130 | Cl | 3-phenyl-1,2,4-oxadiazole | 1.62 | 245 | 195 |
RTI-141 | Cl | 3-(p-anisoyl)-1,2,4-oxadiazole | 1.81 | 835 | 357 |
RTI-143 | Cl | 3-(p-chlorophenyl)-1,2,4-oxadiazole | 4.1 | 4069 | 404 |
RTI-144 | Cl | 3-(p-bromophenyl)-1,2,4-oxadiazole | 3.44 | 1825 | 106 |
βRTI-151 | Me | 3-phenyl-1,2,4-oxadiazole | 2.33 | 60 | 1074 |
αRTI-152 | Me | 3-phenyl-1,2,4-oxadiazole | 494 | — | 1995 |
RTI-154 | Cl | 3-isopropyl-1,2,4-oxadiazole | 6 | 135 | 3460 |
RTI-155 | Cl | 3-cyclopropyl-1,2,4-oxadiazole | 3.41 | 177 | 4362 |
Code | X | 2 Group | DA | NE | 5HT |
---|---|---|---|---|---|
RTI-157 | Me | tetrazole | 1557 | >37K | >43K |
RTI-163 | Cl | tetrazole | 911 | — | 5456 |
RTI-178 | Me | 5-phenyl-oxazol-2-yl | 35.4 | 677 | 1699 |
RTI-188 | Cl | 5-phenyl-1,3,4-oxadiazol-2-yl | 12.6 | 930 | 3304 |
RTI-189 | Cl | 5-phenyl-oxazol-2-yl | 19.7 | 496 | 1116 |
RTI-194 | Me | 5-methyl-1,3,4-oxadiazol-2-yl | 4.45 | 253 | 4885 |
RTI-195 | Me | 5-phenyl-1,3,4-oxadiazol-2-yl | 47.5 | 1310 | >22,000 |
RTI-199 | Me | 5-phenyl-1,3,4-thiadiazol-2-yl | 35.9 | >24,000 | >51,000 |
RTI-200 | Cl | 5-phenyl-1,3,4-thiadiazol-2-yl | 15.3 | 4142 | >18,000 |
RTI-202 | Cl | benzothiazol-2-yl | 1.37 | 403 | 1119 |
RTI-219 | Cl | 5-phenylthiazol-2-yl | 5.71 | 8516 | 10,342 |
RTI-262 | Cl | ||||
RTI-370 | Me | 3-(p-cresyl)isoxazol-5-yl | 8.74 | 6980 | >100K |
RTI-371 RTI-371 3β--2β-[3-isoxazol-5-yl]tropane is a phenyltropane derived drug which acts as a potent and selective dopamine reuptake inhibitor in vitro, yet unusually for this class of compound, both RTI-371 and the closely related compound RTI-370 failed to produce locomotor stimulation in mice... |
Cl | 3-(p-chlorophenyl)isoxazol-5-yl | 13 | >100K | >100K |
RTI-436 | Me | ||||
3.09 | 1960 (1181) | 335 (31) | |||
RTI-470 | Cl | o-Cl-benzothiazol-2-yl | 0.094 | 1590 (994) | 1080 (98) |
RTI-451 | Me | benzothiazol-2-yl | 1.53 | 476 (287) | 7120 (647) |
N-alkyl
Compound | X | 2 Group | config | 8 | DAT | SERT | NET |
FP-β-CPPIT | Cl | 3'-phenylisoxazol-5'-yl | β,β | NCH2CH2CH2F | |||
FE-β-CPPIT | Cl | (3'-phenylisoxazol-5'-yl) | β,β | NCH2CH2F | |||
Altropane Altropane Altropane, is a phenyltropane derivative which acts as a potent dopamine reuptake inhibitor and long-acting stimulant drug... |
F | CO2Me | β,β | NCH2CH=CHF | |||
RTI-310 | I | CO2Me | β,β | N-Prn | 1.17 | ||
RTI-311 | I | CO2Me | β,β | NCH2CH=CH2 | 1.79 | ||
RTI-312 | I | CO2Me | β,β | NBun | 0.76 | ||
RTI-313 | I | CO2Me | β,β | NCH2CH2CH2F | 1.67 | ||
Ioflupane Ioflupane Ioflupane is the International Nonproprietary Name of a phenyltropane compound which is a neuro-imaging radiopharmaceutical drug, used by nuclear medicine physicians for the diagnosis of Parkinson's disease and the differential diagnosis of Parkinson's disease over other disorders presenting... |
¹²³I | CO2Me | β,β | NCH2CH2CH2F | |||
RTI-251 | Cl | CO2Me | β,β | NCH2CO2Et | 1.93 | 10.1 | 114 |
RTI-252 | Cl | CO2Me | β,β | NCH2CH2CO2Et | 2.56 | 35.2 | 125 |
RTI-242 | Cl | β,β (bridged) -C(O)CH(CO2Me)CH2N | 7.67 | 227 | 510 | ||
Bi- and tri-cyclic aza compounds and their uses
N-replaced (S,O,C)
{| class="wikitable"| Compound || X || 2 Group || config || 8 || DA||5-HT||NE
|-
| Tropoxane
Tropoxane
Tropoxane is an aryloxytropane derivative drug developed by Organix Inc, which acts as a stimulant and potent dopamine and serotonin reuptake inhibitor. It is an analogue of dichloropane where the amine nitrogen has been replaced by an oxygen ether link , demonstrating that the amine nitrogen is...
|| Cl,Cl|| CO2Me ||(racemic) β,β || O ||3.3||6.5||No data
|}
Irreversible
IrreversibleCovalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....
(phenylisothiocyanate) binding ligand
RTI-76: 4-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
Nortropanes (N-demethylated)
NS2359NS2359
NS-2359 is a serotonin-norepinephrine-dopamine reuptake inhibitor. It was under development by GlaxoSmithKline as an antidepressant, but was discontinued in 2009 when phase II clinical trials turned up disappointing results and did not support further effort by the company...
(GSK-372,475)
It is well established that electrostatic potential around the para position tends to improve MAT
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...
binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant. Of course, this is not always the case. For an interesting exception to this trend, see the Taxil
RTI-274
RTI-274, or 2β--3α-nortropane is a phenyltropane homologue of paroxetine developed by the group led by F Ivy Carroll in the 1990s.-Introduction:...
document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues which have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.
Code | X | DA | 5HT | NE |
---|---|---|---|---|
RTI-142 | F | 4.39 | 68.6 | 18.8 |
RTI-98 | I | 0.69 | 0.36 | 11.0 |
RTI-110 | Cl | 0.62 | 4.13 | 5.45 |
RTI-173 | Et | 49.9 | 8.13 | 122 |
X | [3H]Paroxetine | [3H]WIN 35,428 | [3H]Nisoxetine |
---|---|---|---|
Ethyl Ethyl Ethyl may refer to:* Ethyl group, a functional group in organic chemistry* Ethyl Corporation, a fuel additive company* Ethanol, also known as ethyl alcohol* Cold Ethyl, a rock band founded by Nicke Andersson... | 28.4 → 8.13 | 55 → 49.9 | 4,029 → 122 |
vinyl Vinyl A vinyl compound is any organic compound that contains a vinyl group ,which are derivatives of ethene, CH2=CH2, with one hydrogen atom replaced with some other group... | 9.5 → 2.25 | 1.24 → 1.73 | 78 → 14.9 |
Ethynyl Ethynyl In organic chemistry, the term ethynyl designates*An ethynyl group .*The ethynyl radical .... | 4.4 → 1.59 | 1.2 → 1.24 | 83.2 → 21.8 |
1-Propyl | 70.4 → 26 | 68.5 → 212 | 3,920 → 532 |
t-propenyl Propenyl Propenyl is a chemical radical of propene .Propenyl groups bind water molecules inside rocks. The amount of water trapped in a rock varies by composition.-References:http://www.biology-online.org/dictionary/Propenyl... | 11.4 → 1.3 | 5.29 → 28.6 | 1,590 → 54 |
c-propenyl | 7.09 → 1.15 | 15 → 31.6 | 2,800 → 147 |
Allyl Allyl An allyl group is a substituent with the structural formula H2C=CH-CH2R, where R is the connection to the rest of the molecule. It is made up of a methylene , attached to a vinyl group . The name is derived from the Latin word for garlic, Allium sativum. Theodor Wertheim isolated an allyl... | 28.4 → 6.2 | 32.8 → 56.5 | 2,480 → 89.7 |
1-Propynyl Propynyl In chemistry, propynyl is an propyl functional group bearing a triple bond. 2-Propynyl is known as propargyl group with the structure of HC≡C−CH2 and 1-propynyl group has the structure of CH3-C≡C-.... | 15.7 → 3.16 | 2.37 → 6.11 | 820 → 116 |
i-Propyl | 191 → 15.1 | 597 → 310 | 75,000 → ? |
2-Propenyl Propenyl Propenyl is a chemical radical of propene .Propenyl groups bind water molecules inside rocks. The amount of water trapped in a rock varies by composition.-References:http://www.biology-online.org/dictionary/Propenyl... | 3.13 → 0.6 | 14.4 → 23 | 1,330? → 144 |
Isomer | 4' | 3' | NE | DA | 5HT |
---|---|---|---|---|---|
β,β | Me | H | 60 → 7.2 | 1.7 → 0.84 | 240 → 135 |
β,β | F | H | 835 → 18.8 | 15.7 → 4.4 | 760 → 68.6 |
β,β | Cl | H | 37 → 5.45 | 1.12 → 0.62 | 45 → 4.13 |
β,α | Me | H | 270 → 9 | 10.2 → 33.6 | 4250 → 500 |
β,α | F | H | 1200 → 9.8 | 21 → 32.6 | 5060 → 92.4 |
β,α | Cl | H | 60 → 5.41 | 2.4 → 3.1 | 998 → 53.3 |
β,α | F | Me | 148 → 4.23 | 13.7 → 9.38 | 1161 → 69.8 |
β,α | Me | F | 44.7 → 0.86 | 7.38 → 9 | 1150 → 97.4 |
"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine
Manifaxine
Manifaxine is a drug developed by GlaxoSmithKline through structural modification of radafaxine, the active metabolite of bupropion. It acts as a norepinephrine-dopamine reuptake inhibitor...
, and reboxetine
Reboxetine
Reboxetine is a drug marketed as an antidepressant for use in the treatment of clinical depression, panic disorder and ADD/ADHD, developed by Pharmacia . Its mesylate salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra...
as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).
Select annotations of above
Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. , , , and .
Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug which is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
binding affinity.
Sister substances
Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidinePiperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
class (a category that includes methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
) or benztropine
Benztropine
Benzatropine , also known as benztropine , is an anticholinergic marketed under the trade name Cogentin which is used in the treatment of Parkinson's disease, parkinsonism, akathisia, and dystonia.- Indications :...
class (such as Difluoropine
Difluoropine
--2β-Carbomethoxy-3α-tropane is a stimulant drug synthesised from tropinone, which acts as a potent and selective dopamine reuptake inhibitor...
: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRI
Dopamine reuptake inhibitor
A dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
s are far removed from being in the phenyltropane structural family, such as Benocyclidine
Benocyclidine
Benocyclidine , or benzothiophenylcyclohexylpiperidine , is a psychoactive drug and research chemical of the arylcyclohexylamine and piperidine chemical classes. It acts a potent and selective dopamine reuptake inhibitor and a stimulant...
or Vanoxerine
Vanoxerine
Vanoxerine is a piperazine derivative which is a potent and selective DRI. GBR-12909 binds to the target site on the DAT ~ 500 times more strongly than cocaine, but simultaneously inhibits the release of dopamine...
.